1. Field of the Invention
The invention relates to novel simplified thioester and isostere analogs of oleoyl coenzyme A which are useful as antiatherosclerotic agents capable of ameliorating atherosclerosis by counteracting the formation or development of atheromatous lesions in the arterial wall of mammals. The invention also relates to the chemical synthesis of the novel compounds disclosed herein. In addition, the invention pertains to novel pharmaceutical compositions for the utilization of these compounds in the treatment of disease in mammals. Further, the invention contemplates methods for treating atherosclerosis in a manner designed to prevent, arrest, or reverse the course of the disease.
2. Description of the Prior Art
Atherosclerosis is a form of arteriosclerosis characterized by lipid accumulation in and thickening of the arterial walls of both medium- and large-sized arteries. Arterial walls are thereby weakened, and the elasticity and effective internal size of the artery is decreased. Atherosclerosis is the most common cause of ischemic heart disease and is of great medical importance since the occlusion of medium- and large-sized arteries diminishes the supply of blood to vital organs such as the heart muscles and the brain. The sequelae to atherosclerosis include ischemic heart disease, heart failure, life-threatening arrythmias, senility, and stroke.
The fact that cholesterol is a major component of atherosclerotic lesions or plaques has been known for more than 100 years. Various researchers have studied the role of cholesterol in lesion formation and development and also, more importantly, whether lesion formation can be prevented or lesion development arrested or reversed Atheromatous lesions have now been shown [Adams, et al., Atherosclerosis, 13: 429 (1974)] to contain a greater quantity of esterified as opposed to unesterified cholesterol than the surrounding undiseased arterial wall. The intracellular esterification of cholesterol with fatty acids via the transesterification reaction of cholesterol and fatty acyl CoA derivatives (primarily oleoyl CoA) is catalyzed by the enzyme fatty acyl CoA:cholesterol acyl transferase or ACAT, and the accumulation and storage of cholesterol esters in the arterial wall is associated with increased activity of this enzyme [Hashimoto and Dayton, Atherosclerosis, 28: 447 (1977)]. In addition, cholesterol esters are removed from cells at a slower rate than unesterified cholesterol [Bondjers and Bjorkerud, Atherosclerosis, 15: 273 (1972) and 22: 379 (1975)]. Thus, inhibition of the ACAT enzyme would diminish the rate of cholesterol esterification, decrease the accumulation and storage of cholesterol esters in the arterial wall, and prevent or inhibit the formation and development of atheromatous lesions.
A number of compounds are reported to be inhibitors of ACAT--catalyzed cholesterol esterification. These include the local anesthetics lidocaine, tetracaine, benzocaine and dibucaine [Bell, Atherosclerosis, 1981, 38, 81], the tranquilizer chlorpromazine [Bell, Exp. Mol. Pathol, 1983, 38, 336], the hypolipidemics clofibrate and benzafibrate [Hudson, Day and Marceglia, Expl. Molec. Pathol, 1982, 36, 156; Hudson, Mojuorder and Day, Expl. Molec. Pathol, 1983, 38, 77], progesterone [Goldstein, Faust, Dygos, Chorvat, and Brown, Proc. Natl. Acad. Sci., 1978, 75, 1877 and Simpson, Burkhart, Arch. Biochem Biophys, 1980, 200, 79], melinamide [Natori, Okazaki, Nakajima, Hirohashi, and Aono, Japan J. Pharmacol 1986, 10, 403], ethyl ester of (z)-N-(1-oxo-9- octadecenyl)-D,L-tryptophan [Heider, Pickens and Kelly, J. Lipid. Res., 1983, 24, 1127], (3-decyl-dimethyl silyl)-N-[Z-(4-methylphenyl)-1-phenethyl] propionamide) [Ross, Go, Heider and Rothblat, J. Biol. Chem, 1984, 259, 815] and N,-2,4-difluorophenyl-N-n-heptyl-N-(4-neopentyl) benzyl urea [DeVries, Schaffer, Langis, Dutia, Wang, Bloom and Katucs, A.S.J. Med. Chem, 1986, 29, 1131].